Background: Endotoxin tolerance describes the phenomenon whereby prior lipopolysaccharide (LPS) exposure attenuates inflammatory responses to subsequent LPS challenge. Studies have reported the involvement of different mediators of the toll-like receptor (TLR)-4 signaling pathway in endotoxin tolerance. Methods: We first examined dose- and time-dependent production of cytokines following LPS treatment and then examined cytokine production in BV2 cells pretreated with 5 ng/mL LPS for 24 h, followed by secondary challenge with 1 µg/mL LPS for four hours. To examine which inflammatory cytokine could induce tolerance, we pretreated BV2 cells with 1 µg/mL IL-1β, IL-6, or TNF-α for 24 h, followed by secondary challenge with 1 μg/mL LPS for four hours, and then examined cytokine production by ELISA. Results: Our data showed that LPS induced dose- and time-dependent production of IL-1β, IL-6, and TNF-α. Pretreatment with 5 ng/mL LPS significantly reduced the production of IL-1β and TNF-α in response to secondary challenge, while IL-6 production was slightly enhanced. We also found that pretreatment with IL-1β did not attenuate production of TNF-α but slightly enhanced IL-6 following secondary challenge with 1 µg/mL LPS. In contrast, pretreatment with IL-6 or TNF-α significantly attenuated subsequent LPS-induced IL-1β production without affecting the production of the other. Conclusions: Endotoxin tolerance in BV2 microglial cells selectively suppresses IL-1β and TNF-α while preserving IL-6 production. Both IL-6 and TNF-α independently induce tolerance specifically to IL-1β, suggesting negative feedback regulations. These findings reveal that endotoxin tolerance involves selective rather than global suppression of inflammatory mediators and cross-regulation between LPS and cytokine-induced signaling pathways.
Kadiyala et al. (Wed,) studied this question.